EFFECTS OF LIPID-A ON CALCIUM HOMEOSTASIS IN RENAL PROXIMAL TUBULES

It is clear that lipopolysaccharides (LPS) are responsible for the mul tiorgan failure often associated with endotoxemia. However, little is known of the direct effects of LPS on kidney cells. We examined the ef fects of lipid A, the biologically active component of LPS, on rat pro ximal tubule Ca++ homeostasis. Lipid A produced a rapid, transient, co ncentration-dependent rise in intracellular Ca++ concentration, [Ca++] (i), as monitored by fura-2. At 50 mu g/ml [Ca++](i) rose to 138 +/- 1 2 nM (n = 4) above basal [Ca++]i levels. The response to lipid A was n ot significantly inhibited by chelating extracellular Ca++ with EGTA ( 5 mM). However, the rise in [Ca++](i) was significantly inhibited by - (N,N-dimethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride) and t hapsigargin (17 +/- 7 nM and 13 +/- 9 nM rise, respectively; P < .05). These data indicate that the rise in [Ca++](i) induced by lipid A is due to release of intracellular stores, and not extracellular influx. We also examined the role of inositol 1,4,5-trisphosphate in the lipid A response. Lipid A caused a time-dependent increase in inositol 1,4, 5-trisphosphate that paralleled the rise in [Ca++](i), suggesting the release in [Ca++](i) is through an inositol 1,4,5-trisphosphate-mediat ed release of intracellular stores. The ability of lipid A to alter Ca ++ homeostasis suggests a potential for LPS to directly alter proximal tubule physiology and renal function in vivo.